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1.
J Neurooncol ; 167(2): 349-359, 2024 Apr.
Article En | MEDLINE | ID: mdl-38427131

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.


Central Nervous System Neoplasms , Pandemics , Humans , Retrospective Studies , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/therapy , Patient Care Team , Referral and Consultation
2.
J Clin Oncol ; 42(13): 1542-1552, 2024 May 01.
Article En | MEDLINE | ID: mdl-38335473

PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.


Brain Neoplasms , Glioma , Histones , Mutation , Humans , Adult , Female , Male , Adolescent , Middle Aged , Young Adult , Glioma/genetics , Glioma/drug therapy , Glioma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Child , Histones/genetics , Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/drug therapy , Child, Preschool , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Pyridones/therapeutic use
3.
Neurooncol Adv ; 6(1): vdae014, 2024.
Article En | MEDLINE | ID: mdl-38420615

Background: A significant unmet need exists for the treatment of glioblastoma, IDH-wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with MGMT promoter-methylated high-grade glioma. Methods: A total of 24 patients (GBM, IDH-wildtype = 22; Grade 4 astrocytoma, IDH-mutant = 1; Grade 3 astrocytoma, IDH-mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles. Results: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P = .06). Conclusions: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter-methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.

4.
Neurologist ; 28(3): 135-142, 2023 May 01.
Article En | MEDLINE | ID: mdl-37027168

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare, often curable neoplasm, often initially presenting in acute care settings by nonneuroscience specialized physicians. Delays in the recognition of specific imaging findings, lack of appropriate specialist consultation, and urgent incorrect medication administration can delay necessary diagnosis and treatment. REVIEW SUMMARY: In this paper, the reader is moved quickly from the initial presentation to the diagnostic surgical intervention for PCNSL in a manner analogous to the experience of clinicians in the frontline setting. We review the clinical presentation of PCNSL, its radiographic features, the effect of prebiopsy steroids, and the role of a biopsy in the diagnosis. In addition, this paper revisits the role of surgical resection for PCNSL and investigational diagnostic studies for PCNSL. CONCLUSION: PCNSL is a rare tumor that is associated with high morbidity and mortality. However, with appropriate identification of clinical signs, symptoms, and key radiographic findings, the early suspicion of PCNSL can lead to steroid avoidance and timely biopsy for rapid administration of the potentially curative chemoimmunotherapy. Surgical resection presents the potential for improving outcomes for patients with PCNSL, however, this remains controversial. Further research into PCNSL presents the opportunity for better outcomes and longer livelihoods for patients.


Central Nervous System Neoplasms , Lymphoma , Humans , Lymphoma/diagnostic imaging , Lymphoma/therapy , Central Nervous System Neoplasms/diagnostic imaging , Central Nervous System Neoplasms/therapy , Steroids/therapeutic use , Magnetic Resonance Imaging/methods , Central Nervous System/pathology
5.
Neurohospitalist ; 12(3): 567-570, 2022 Jul.
Article En | MEDLINE | ID: mdl-35755215

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare, delayed complication of cranial radiation therapy that consists of migraine-like headaches and focal neurologic deficits such as visual loss, aphasia, hemiparesis, hemisensory loss, and unconsciousness. SMART syndrome may be mistaken for tumor recurrence, radiation necrosis, and stroke. Timely recognition of SMART syndrome prevents unnecessary brain biopsies and enables appropriate anticipatory guidance. We present a 38 year-old right handed male with new headaches, vertigo, visual symptoms, and left-sided paresthesias. Neuroimaging revealed a heterogeneously enhancing mass with invasion into the transverse sinus, diagnosed as an epithelioid hemangioendothelioma by surgical pathology. After resection, the patient underwent proton beam radiation for maximal tissue-sparing. Six months later, he developed radiation necrosis. After another year, he developed recurrent headaches with transient language difficulties and blurry vision during each headache. Neuroimaging was consistent with SMART syndrome, and the patient was started on valproate. Verapamil was added after a second attack. The patient's headaches improved, but he remains dyslexic. Subsequent imaging shows resolution of gyriform contrast enhancement and continued left temporo-occipital T2/FLAIR hyperintensity. We present a case of early SMART syndrome following proton beam radiotherapy, as well as the dual occurrence of radiation necrosis and SMART syndrome in this individual. Radiation necrosis and SMART syndrome are known complications of radiotherapy, with the latter less well-described. We discuss a possible shared pathophysiology involving endothelial cell dysfunction and impaired cerebrovascular autoregulation, and we question whether proton RT increases risk of early SMART syndrome development.

6.
J Neurooncol ; 155(3): 297-306, 2021 Dec.
Article En | MEDLINE | ID: mdl-34689306

PURPOSE: Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naïve and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial. METHODS: Recurrent high-grade glioma patients were stratified based on WHO grade (4 vs. < 4) and prior exposure to bevacizumab (yes vs. no). Eligible patients received radiation using a simultaneous integrated boost technique (55 Gy to enhancing disease, 45 Gy to non-enhancing disease in 25 fractions) with bevacizumab 10 mg/kg every 2 weeks IV and temozolomide 75 mg/m2 daily followed by maintenance bevacizumab 10 mg/kg every 2 weeks and temozolomide 50 mg/m2 daily for 6 weeks then a 2 week holiday until progression. Primary endpoint was overall survival. Quality of life was studied using FACT-Br and FACT-fatigue scales. RESULTS: Fifty-four patients were enrolled. The majority (n = 36, 67%) were bevacizumab pre-exposed GBM. Median OS for all patients was 8.5 months and 7.9 months for the bevacizumab pre-exposed GBM group. Patients ≥ 36 months from initial radiation had a median OS of 13.3 months compared to 7.5 months for those irradiated < 36 months earlier (p < 0.01). FACT-Br and FACT-Fatigue scores initially declined during radiation but returned to pretreatment baseline. Treatment was well tolerated with 5 patients experiencing > grade 3 lymphopenia and 2 with > grade 3 thrombocytopenia. No radiographic or clinical radiation necrosis occurred. CONCLUSIONS: Re-irradiation with bevacizumab and temozolomide is a safe and feasible salvage treatment for patients with large volume bevacizumab-refractory high-grade glioma. Patients further from their initial radiotherapy may derive greater benefit with this regimen.


Brain Neoplasms , Chemoradiotherapy , Glioma , Re-Irradiation , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Fatigue , Glioma/drug therapy , Glioma/radiotherapy , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/radiotherapy , Prospective Studies , Quality of Life , Temozolomide/therapeutic use
7.
Curr Treat Options Oncol ; 21(9): 77, 2020 07 30.
Article En | MEDLINE | ID: mdl-32734428

OPINION STATEMENT: Corticosteroids have been essential in the management of brain tumor patients for decades, primarily for the treatment of peritumoral cerebral edema and its associated neurologic deficits. Dexamethasone is the drug of choice with standard practice being administration up to four times per day, however, because of its long biologic half-life and high potency, once or twice a day dosing is likely adequate in patients without elevated intracranial pressure. The length of corticosteroid treatment should be limited to the shortest period of time to minimize the risk of potential toxicities that can significantly affect quality of life, as well as to avoid a possible detrimental impact on survival in high-grade glioma patients and abrogation of the effect of immunotherapy. Agents such as bevacizumab should be considered in patients who are unable to wean completely off of steroids as well as those who have symptomatic edema and are on immunotherapy. Several other agents have been studied without much success. An increased understanding of the complex pathophysiology of peritumoral vasogenic edema is critically needed to discover new agents that are safer and more effective.


Adrenal Cortex Hormones/therapeutic use , Brain Neoplasms/therapy , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/pharmacokinetics , Brain Edema/drug therapy , Brain Edema/etiology , Brain Edema/prevention & control , Brain Neoplasms/complications , Brain Neoplasms/diagnosis , Brain Neoplasms/etiology , Clinical Decision-Making , Combined Modality Therapy , Disease Management , Humans , Treatment Outcome
8.
J Neurol Sci ; 411: 116706, 2020 Apr 15.
Article En | MEDLINE | ID: mdl-32007755

Central nervous system (CNS) metastasis from systemic cancers can involve the brain parenchyma, leptomeninges (pia, subarachnoid space and arachnoid mater), and dura. Leptomeningeal metastases (LM), also known by different terms including neoplastic meningitis and carcinomatous meningitis, occur in both solid tumors and hematologic malignancies. This review will focus exclusively on LM arising from solid tumors with a goal of providing the reader an understanding of the epidemiology, pathophysiology, clinical presentation, prognostication, current management and future directions.


Meningeal Carcinomatosis , Meningeal Neoplasms , Meningitis, Bacterial , Neoplasms , Arachnoid , Dura Mater , Humans , Meningeal Carcinomatosis/epidemiology , Meningeal Neoplasms/epidemiology , Meninges
9.
Neuro Oncol ; 22(4): 470-479, 2020 04 15.
Article En | MEDLINE | ID: mdl-31711239

BACKGROUND: Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying. METHODS: The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide. RESULTS: In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003). CONCLUSIONS: With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.


Brain Neoplasms , Glioblastoma , Supratentorial Neoplasms , Aged , Brain Stem , Humans , Temozolomide
11.
Curr Treat Options Oncol ; 16(8): 38, 2015 Aug.
Article En | MEDLINE | ID: mdl-26143268

OPINION STATEMENT: Treating patients with brain tumors can be divided into tumor-directed therapies, the management of tumor-related symptoms and complications and the psychosocial aspect of patient care. In this review, we will discuss the management of disease and treatment-related complications, which can negatively impact patient quality of life and functional status. Brain edema is a common complication or brain tumors and often causes more symptoms than the tumor itself. Treatment options are limited to the use of corticosteroids, which although effective have a plethora of side effects, so the goal should be the lowest dose that maximizes symptoms. Seizures are more common in lower grade brain tumors and treatment should be limited to patients who have seizures using agents that do not affect the metabolism of other drugs, especially chemotherapies. Blood clots are also common in patients and although there is a "fear" of tumoral bleeding, this is not a frequent occurrence; hence, using anticoagulants should be routinely used in patients who experience this complication.


Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/complications , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Edema/diagnosis , Brain Edema/etiology , Brain Edema/therapy , Central Nervous System Neoplasms/therapy , Disease Management , Humans , Seizures/diagnosis , Seizures/etiology , Seizures/therapy , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/therapy
12.
Neurology ; 85(2): 172-6, 2015 Jul 14.
Article En | MEDLINE | ID: mdl-26070342

OBJECTIVE: Due to the burden of neurologic disease, there is high demand for neurologists, child neurologists, and neurosurgeons. Only 2.6% of graduating medical students matched in neuromedicine residencies in 2014. This number will not likely meet the needs of the population or the projected shortfall. To compensate for this, the medical education system has an obligation to ensure competence in neuromedicine for all trainees and mentorship for students pursuing training in the field. We aim to evaluate the state of the neurology clerkship in US medical schools and how this impacts graduates entering the field. METHODS: Publicly available curricula of 158 US medical schools were reviewed. Presence of a required neurology clerkship, its duration, and the year offered were tabulated, as were the availability of child neurology and neurosurgery electives and affiliated neuromedicine residencies. The total graduating students from each medical school matching into neuromedicine residencies for 2011-2014 were recorded. Repeated-measure analysis of variance was used to assess the relationship of these variables to number of students matching into the collective neuromedicine. RESULTS: All but 4 schools (97%) published clerkship information. Neurology was a required clerkship at 56% of reporting institutions. Residency match data were not published from 53 schools (35%) and these were excluded from the analysis. In the remaining schools, all variables showed a relationship to students matching in neuromedicine residencies. CONCLUSIONS: The presence of a required neurology clerkship and opportunities for students to explore neuromedicine during medical school correlates with students matching into neuromedicine residencies.


Clinical Clerkship , Education, Medical, Undergraduate , Neurology/education , Career Choice , Education, Medical, Graduate , Humans , Internship and Residency/statistics & numerical data , Neurosciences/education
13.
World Neurosurg ; 82(6): 938-44, 2014 Dec.
Article En | MEDLINE | ID: mdl-24834873

OBJECTIVE: To develop an understanding of the availability of the formal clinical neuro-oncology educational opportunities for medical students. METHODS: The curriculum websites of all medical schools accredited by the Liaison Committee on Medical Education were reviewed for the presence of clinical neuro-oncology electives as well as other relevant data. RESULTS: Ten (6.8%) of medical schools accredited by the Liaison Committee on Medical Education offer formal neuro-oncology electives. Half are clustered in the Midwest. Forty percent are at institutions with neuro-oncology fellowships. All are at institutions with neurosurgery and neurology residency programs. CONCLUSIONS: Formal clinical neuro-oncology elective opportunities for medical students in the United States and Canada are limited. Additional such opportunities may be of value in the education of medical students.


Medical Oncology/education , Neurology/education , Students, Medical/statistics & numerical data , Adult , Canada , Curriculum , Female , Humans , Internship and Residency/statistics & numerical data , Male , Personnel Selection , United States , Young Adult
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